Cancer Chemoprevention The Role of Resveratrol

The word cancer refers to any malignant tumor of any part of the body. According to Willis, a cancer, or a neoplasm is an abnormal mass of tissue the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after the cessation of the stimuli which evoked the change. A cancer can therefore be said to be a disorder of cell growth and behavior. Cancers are one of the major causes of deaths occurring from medical conditions. Overall, it is estimated that about 1.4 million new cancer cases will occur in 2006, and 565,000 people will die of cancer in the United States. Recent estimates also from the World Health Organization suggests that cancer leads to about 12 of all human deaths, claiming over 6,000,000 lives each year, and that cancer is the second leading cause of death specifically in the United States, being responsible for approximately one in every four deaths (Aggarwal  Shishodia). Being then a serious condition, the ultimate cause of cancer needs to be found. Because cancer occurs at the cellular level, the cause has to be found at this level.

The Multistep Carcinogenesis Theory (Molecular Basis)
It has been postulated that carcinogenesis is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutations. Continuous buildup of somatic mutations in a particular single cell line over a long period of time results in a morphologic progression from a normal epithelium to hyperproliferative, dysplastic and finally the development of neoplastic epithelium.

Figure 1. Molecular model for the evaluation of colorectal cancers through the adenoma-carcinoma sequence.

Fig. 1 above clearly illustrates this diagrammatically with respect to the evolution of colorectal cancers through the adenoma-carcinoma sequence. DNA damage from accumulated exposure to carcinogens become obvious during the development of neoplasia. Several researchers have discovered the role of some specific genes in neoplastic transformation. These genes, when altered, ultimately result in cancer. There are four classes of these genes

Growth-promoting proto-oncogenes  which encode growth factors, growth factor receptors, proteins involved in signal transduction, cell cycle regulators and nuclear regulatory proteins.

Growth-inhibiting tumor suppressor genes  encoding proteins that regulate nuclear transcription and cell cycle such as the Rb gene, p53, BRCA-1 and BRCA-2, NF-1 and NF-2, APC, WT-1, TGF- receptor, and p16(INK4a).

Apoptotic genes (genes that regulate programmed cell death) such as bcl-2, bcl-xS, bcl-xL, bad, bid, and bax.

DNA-repair genes.

These genes affect all the stages of tumor progression. The initiation stage is fast and irreversible. It is at this stage that the cells DNA is bound and damaged, that is, mutation occurs at this stage. Promotion, which involves epigenetic mechanisms, leads to premalignancy and is generally irreversible while progression, which is due to genetic mechanisms, is the period between premalignancy and the cancer and is also generally irreversible.

Cancer Prevention Strategies
A lot of scientists and researchers believe that most cancers can be prevented, if not cured. As the popular maxim goes, Prevention is better than cure, what then are the prevention modalities in existence There are three major cancer prevention strategies the primary prevention strategy, the secondary prevention strategy and the tertiary prevention strategy. The ultimate aim of these prevention strategies is to reduce the incidence rate of cancers and therefore the fatalities caused by this condition. Primary prevention strategies involve the elimination of the etiologic and risk factors associated with the development of cancers. They prevent de novo cancer formation in an otherwise healthy individual. This may involve lifestyle modifications and the avoidance of some causative agents such as carcinogens being encountered in every individuals everyday life. Secondary prevention strategies involve the use of natural or synthetic substances to actually reduce the risk or spread of malignant tissue transformation in individuals with known premalignant lesions. One major secondary prevention strategy is cancer chemoprevention. Tertiary prevention focuses on the prevention of SPTs in patients cured of their initial cancer or individuals definitively treated for their premalignant lesions.

Cancer chemoprevention is defined as the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. This mode of prevention employs the use of a pharmacological approach to intervene in the process of carcinogenesis and the basis of this trial is a hypothesis that interruption of any stage of the process of cancer formation will reduce the incidence rates of cancers. Although the carcinogenic process may be driven by mutation, there are clearly many epigenetic variables, particularly those relating to the action of autocrine, paracrine, and endocrine regulatory molecules, which can also be important determinants during the twenty year or more latent period before invasion and metastasis occur. It has been found out that alterations or modulations of these regulatory pathways involved in cancer development by the use of agents that block mutations of DNA presents huge potentials for the prevention of cancer.  The concept of cancer chemoprevention, based on the successful outcome of many clinical trials, presents an attractive therapy for impeding or reversing malignant transformation.

Cancer chemoprevention trials, conducted to test chemopreventive substances, are usually conducted on high risk groups in order to test the efficacy of these agents. According to Sporn and Suh (2000), the credibility of the use of cancer chemoprevention as a serious and practical approach to the control of cancer has been greatly enhanced by the publication, over the past two years, of the results of three randomized clinical trials in the field of breast cancer. These trials were conducted using three different agents which were found to be effective in the control of cancer. These agents are raloxifene, tamoxifene, and 4-hydroxyphenylretinamide (fenretinide).

One of the most important factors in conducting chemopreventive trials is the use of intermediate markers. Because cancer progression takes a long time (years) to become obvious, the evaluation of these agents might become tedious. Monitoring intermediate markers that correlate with a reduction in cancer incidence would allow a more expeditious evaluation of potentially active chemopreventive agents. A good potential source of intermediate markers is the premalignant lesions that appear before the full-blown cancer becomes obvious. The disappearance of these premalignant lesions, during the process of conducting these trials, can be said to be proportional to the efficacy of the chemopreventive agents. According to Tsao et al (2004), they may serve as intermediate endpoints for chemoprevention trials. One of these intermediate markers is intraepithelial neoplasia (IEN), which is defined as a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer, and that predicts a substantial likelihood of developing invasive cancer. The American Association of Cancer Research Task Force defined prevention and regression of IEN as being an important clinical trial endpoint.

As mentioned earlier, before a full blown cancer can develop, there will be the alterations of a series of processes. Some of these defects will be discussed below. The essence of this is to understand the pathways of cancer formation how they can be tackled by the use of chemopreventive agents to prevent or delay the development of neoplasia.

Molecular Basis of Cancer
It has been found out that nonlethal genetic damage lies at the heart of carcinogenesis. The genetic damage (mutations) may be as a result of the actions of environmental agents such as radiation, chemicals, biologic agents (viruses), or hereditary. The genetic hypothesis of cancer implies that a tumor mass results from the clonal expansion of a single progenitor cell that has incurred the damage (i.e., tumors are monoclonal). This means that just a single cell is required to mutate before it begins mass replication to form a tumor mass.

Also, a mutation in any member of the four classes of regulatory genes  protooncogenes (growth-promoting), tumor suppressor genes (growth inhibiting), apoptotic genes, and DNA repair genes  is required for tumor development. Unlike the tumor suppressor genes that require damages in both alleles before transformation can occur, mutant alleles of the growth promoting factors are said to be dominant because only an allele is required to become mutated in order to cause transformation. Apoptotic genes are also dominant, just like the protooncogenes. They may also behave like tumor suppressor genes. On the other hand, damage of the DNA repair genes influences the survival and proliferation of cells. This damage also influences the ability of the cell to repair nonlethal damage in other genes. And like the tumor suppressor genes, two hits are needed (i.e., damage in both alleles) in order to induce genetic instability.

The process of carcinogenesis involves many steps at both the morphologic (phenotypic) and genetic levels. At the genetic level, tumor progression results from the buildup of genetic damage that is favored in most instances by alterations in DNA repair.

Basis of Cancer Chemoprevention
Just like every other pharmacological agent, the use of chemopreventive agents depends on a number of factors. One major factor that has to be considered is the mechanism of action of the agent at all levels, that is, the genetic (molecular) level up to the systemic level, and even the organism as a whole. Based on this, there are different classes of chemopreventive agents. Some of them are

Class 1  Selective inhibitors of cyclooxygenase (COX-2). Cyclooxygenases are responsible for the synthesis of prostaglandins from arachidonic acid. The fact that inflammation has a role in carcinogenesis (causes a premalignant change) has led to the development of many new pharmacologic agents. One of these agents is Celecoxib. Celecoxib has been shown to prevent colon carcinogenesis caused by azoxymethane in a standard rat model, and is now in clinical trial in cohorts of patients at high risk, such as those with familial adenomatous polyposis, or hereditary non-polyposis colorectal cancer syndromes.

Class 2  These are the Selective Estrogen Receptor Modulators (SERMs). Examples include raloxifene and tamoxifene.

Class 3  Retinoids. These substances are normal regulators of the cellular differentiation and proliferation. The retinoids bind selectively to retinoid X receptors. These receptors have the ability to heterodimerize with most other components of the nuclear receptor superfamily. Some of the members of the nuclear receptor superfamily apart from the retinoid acid receptors are thyroid receptors, vitamin D receptors, and the peroxisome proliferator-activated receptor- (PPAR-)   also called the  orphan  receptor. The major role of the retinoid X receptors is to modulate the effects of most other receptors. These receptors act as ligand-activated transcription factors when bound to retinoids and their mechanisms essentially depend on the retinoids capacity to regulate gene expression through nuclear transduction signal modulation mediated by nuclear retinoid receptors.

Class 4   Peroxisome proliferator-activated receptor- (PPAR-) ligands. Because of the ability of PPAR- to bind both fatty acids and prostaglandins, it has also become a target for investigation in colon carcinogenesis (Sporn  Suh, 2000). The PPAR- has been exploited in the treatment of Diabetes mellitus type 2 because its ligands can stimulate cells, particularly, adipocytes, to the adipogenic effect of insulin. However, recent researches have indicated the effect of troglitazone on the differentiation of human liposarcoma cells.

Most of these classes of drugs show synergism among each other, such that, they encourage the use of combination chemoprevention therapy. Combination chemoprevention is said to be a state whereby one achieves significant synergism of two drugs to obtain a desired preventive effect, while minimizing the toxic side effects of the individual components of the combined regimen. Most new classes of chemopreventive agents that are being developed today combine the effects of different drug categories to produce a single synergistic, efficacious, and less toxic agent. It is appreciated that an effective and acceptable chemopreventive agent should have certain properties (a), little or no toxic effects in normal and healthy cells (b), high efficacy against multiple sites (c), capability of oral consumption (d), known mechanism of action (e), low cost and (f), acceptance by human population (Aziz, Kumar). One of such chemopreventive agents is Resveratrol.

Cancer Chemoprevention by Resveratrol
Resveratrol is a naturally occurring substance found in grapes, red wine, berries, and some other food products. It is a phytoalexin (polyphenolic antioxidant) found to have cancer chemopreventive activities in a number of trials. Historically, the ancient Chinese and the Japanese have used root mixtures of Plygonum cuspidatum (which is now known to contain Resveratrol) to combat skin and liver disease. The cancer chemopreventive activities was first brought to light by Jang et al who demonstrated that demonstrated that Resveratrol possesses cancer chemopreventive activity against all the three major stages of carcinogenesis, i.e., initiation, promotion and progression (Cai, Udeani, Slowing et al, 1997.).

    trans-Resveratrol        cis-Resveratrol
Figure 2. The chemical structure of cis- and trans-Resveratrol
Resveratrol, also known as trans-resveratrol, has the chemical name of 3,5,4-trihydroxystilbene. The chemical structure of this compound is relevant in its mechanism of action. Resveratrol has two forms  the cis and the trans form. Because of the presence of multiple OH groups on the structure, resveratrol is classified as a polyphenol. Polyphenols are antioxidants that can react with a free radical to produce a more stable compound.

According to Jang et al (1997), Resveratrol has the following properties (i), acts as an antioxidant and antimutagen (ii), induces phase II drug-metabolizing enzymes (anti-initiation activity) (iii), mediates anti-inflammatory effects (iv), inhibits cyclooxygenase and hydroperoxidase functions (anti-promotion activity) and (iv), induces human promyelocytic leukemia cell differentiation (anti-progression activity). Apart from these properties, resveratrol also has antiproliferative properties on epithelial cells.

Resveratrol is also associated with a new concept  the French paradox. It has been discovered that the incidence rate of some co-morbid conditions such as coronary heart disease and some types of cancers is very low among members of the French population. This is in spite of the fact that the average French diet consists of high fat-containing foods such as butter, cheese, cream, etc. When the average French diet was compared to a typical American diet, it was found out that a typical French diet contains approximately 15 more saturated fat than an American diet. This coupled with the fact that Americans exercise more than the French, it should be expected that more heart conditions should be recorded. However, the reverse is the case. This paradox has been attributed to the consumption of red wine by French people.

Role of Resveratrol in Cancer
A lot of epidemiological studies have been conducted on the effect of resveratrol in preventing cancers. This effect varies among different types of cancers. Each of these cancers will be discussed below, along with the resveratrol effect.

1. Resveratrol and Breast Cancer
Breast cancer is one of the most prevalent and deadly cancers. It a major cause of deaths worldwide. It is also the most common cancer in women. High incidence rates of breast cancers have also been reported among the male population. It is estimated that 203,500 new cases of invasive breast cancer will be diagnosed in 2002, and that 39,600 women will die from the disease. The associated risk factors include older age, higher body mass index, alcohol consumption, hormone replacement, prior radiation exposure, nulliparity, family history, gene carrier status of BRCA1 and BRCA2, and prior history of breast neoplasia.

Resveratrol has been found to exert a direct antiproliferative role on the rapidly proliferating breast cancer cells in spite of the presence of estrogen receptors on the cells. Several in vitro studies have shown that resveratrol inhibited growth of 4T1 breast cancer cells in a dose- and time dependent manner, however, resveratrol was found to have no effect on the growth of 4T1-implanted tumors or its metastasis when administered intraperitoneally daily (1, 3, or 5 mgkg) for 23 days starting at the time of tumor inoculation.

The controversy exists that resveratrol is either an estrogen receptor (ER) agonist or antagonist. It is however presumed that resveratrol works with the estrogen receptor to block its activation. Also, resveratrol has been found to inhibit the proliferation of a particular ER negative human breast carcinoma cell line MDAMB-468. In addition, resveratrol significantly elevated the expression of the growth inhibitor TGF-2 mRNA without changes in TGF-1 and TGF-3 expression. These data suggested that resveratrol inhibits proliferation by altering autocrine growth modulator pathways in breast cancer cells.

2. Resveratrol and Prostate Cancer
Prostate cancer has become the most frequently diagnosed cancer and the second leading cause of cancer-related death for men in the United States. In the United States, the estimated incidence for the year 2004 was 230,110 new cases and 29,900 deaths while the lifetime risk of developing prostate cancer is 19. The risk factors for developing prostate cancer include older age, family history, race and ethnicity, and possibly dietary fat. Because of the increasing incidence rates of prostate cancer, several therapies have been sought in order to combat this cancer.

Several researches have evaluated the effect of resveratrol on prostate cancer development. The major effect of this agent is to inhibit the proliferative abilities of the malignant cells. Hsieh and Wu (1999) investigated the effects of resveratrol on growth, induction of apoptosis, and modulation of prostate-specific gene expression using DU-145, PC-3, and JCA-1 human prostate carcinoma cells. The results of this study have suggested that resveratrol inhibits the growth of CaP cells by inducing apoptosis, and also by inhibiting mitogenesis in a specific way.

Recent studies showed the unique ability of resveratrol to exert opposing effects on two important processes in cell cycle progression, induction of S phase and inhibition of DNA synthesis in prostate carcinoma cells. A mechanistic basis for the efficacious role of resveratrol in prostate cancer has been developed by Seeni et al (2008). The study was conducted using the Transgenic Rat for Adenocarcinoma of Prostate (TRAP) model.  This in vivo experiment featured the rat probasin promoterSV T 40 antigen. It was found out that resveratrol suppressed prostate cancer growth and induction of apoptosis through androgen receptor (AR) down-regulation, without any sign of toxicity (Seeni et al, 2008). Resveratrol not only downregulated androgen receptor (AR) expression but also suppressed the androgen responsive glandular kallikrein 11 (Gk11), known to be an ortholog of the human prostate specific antigen (PSA), at the mRNA level (Seeni et al, 2008). The results of the experiment are stated below

Table 2. Incidences of Prostate Adenocarcinomas in TRAP Rats Treated with Resveratrol
Source Seeni et al (2008)

TreatmentNo. of ratsIncidence of Adenocarcinoma ()VentralLateralDorsalAnteriorControl1211 (92)4 (33)00Resveratrol 50gml1210 (83)2 (17)00Resveratrol 100gml1210 (83)5 (42)00Resveratrol 200gml129 (75)2 (17)003. Resveratrol and Lung Cancer

The leading cause of cancer deaths in the world is lung cancer. For the year 2004, 173,770 new cases and 160,440 deaths are anticipated in the United States (Tsao et al, 2004). Lung cancer is also one of the most preventable forms of cancer because its most important risk factor, smoking, can easily be avoided in both youths and adults. Other risk factors for lung cancer, apart from smoking, includes exposure to carcinogenic agents such as polycyclic aromatic hydrocarbons, asbestos, radon, nickel, benzoapyrene, etc exposure to ionizing radiation and infectiousinflammatory conditions of the lungs such as chronic obstructive pulmonary diseases (COPD)  chronic bronchitis and emphysema.

A study carried out by Kimura and Okuda (2000) evaluated the effects of stilbene glucosides extracted from some grapes on tumor growth and lung metastasis in mice bearing highly metastatic Lewis lung carcinoma (LLC) tumors. It was found out that tumor growth in the right hind paw and lung metastasis were inhibited by oral administration of resveratrol 3-O-D-glucoside and 2,3,5,4-tetrahydroxystilbene-2-O-D-glucoside for 33 consecutive days, in LLC-bearing mice (Kimura  Okuda, 2000). The results of the study are as follows as stated by Aziz and Kumar (2003)

Inhibition of DNA synthesis in LLC cells by Resveratrol 3-O-D-glucoside at a concentration of 1000M, but not at lower concentrations.

Inhibition of DNA synthesis in LLC cells by 2,3,5,4-Tetra-hydroxystilbene- 2-O-D-glucoside also (IC50  81M).

In addition, both stilbene glucosides were found to inhibit the formation of capillary-like tube networks (angiogenesis) of HUVECs at concentrations of 100-1000M.

The conclusion of the authors of this study shows that the activities of these resveratrol variants may be as a result of inhibition of DNA synthesis in LLC cells and the inhibition of angiogenesis in HUVECs.

4. Resveratrol and Skin Cancer
According to the World Cancer Report, skin cancer constitutes 30 of all newly diagnosed cancers in the world and solar ultraviolet (UV) radiation, particularly its ultraviolet B (UVB) component (290320nm), is an established cause of 90 of skin cancers (Aziz, Reagan-Shaw  Wu et al, 2005). Associated risk factors for skin cancer include childhood and chronic sun exposure, individual susceptibility with red or blond hair and fair-skinned phenotype, older age, polycyclic aromatic hydrocarbon, immunocompromised status, or xeroderma pigmentosum.

A study carried out by Aziz et al (2003) evaluated the chemopreventive effects of resveratrol on the development of skin cancers in hairless mice. SKH-1 hairless mice were subjected to chronic UVB exposure (180mJcm2, twice weekly) for a period of 28 weeks resulting in the development of a variety of skin tumors. Two protocols were observed in conducting this experiment. The results, as shown in Figure 3 below, clearly demonstrate that topical application of resveratrol on mouse skin (pre- and post-treatments) resulted in a highly significant inhibition of tumor incidence ( mice with tumors) and a significant delay in the onset of tumorigenesis (Aziz et al, 2003). Also, resveratrol treatment also significantly reduced tumor multiplicity (tumorsmouse), measured as a function of time, compared with UVB alone group.

In another recent study, the involvement of the nuclear transcription factor B pathway in the development of skin cancer and the chemoprevention of UV damage by resveratrol was demonstrated. Based on this research on normal human epidermal keratinocytes, resveratrol was found to block UVB (40mJcm2)-mediated activation of NF-B in a dose (5, 10 and 25M resveratrol for 24 h)- as well as time- (5M resveratrol for 12, 24 and 48 h) dependent fashion.

Resveratrol treatment of keratinocytes was also found to inhibit UVB-mediated (i), phosphorylation and degradation of IB and (ii), activation of IKK. Based on these data, we suggested that NF-B pathway plays a critical role in the chemopreventive effects of resveratrol against the adverse effects of UV radiation including photocarcinogenesis.

Figure 3. Effect of resveratrol treatments on UVB exposure-mediated skin tumorigenesis in SKH-1 hairless mice. Source Aziz et al (2003).

5. Resveratrol and Colorectal Cancers
Cancers of the colon are rated to be the third leading cause of cancer-related death in both men and women. Epidemiological studies have shown that colon cancers are more prevalent in areas where diets low in fiber, folate and calcium are consumed. Other risk factors associated with colon cancers include obesity, sedentary lifestyle, male gender, alcohol, smoking, fatty foods, etc. Stronger, albeit less prevalent, risk factors that are more significant include inflammatory bowel disease and genetic disorders such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC).

Studies conducted by Schneider et al (2000) investigated the effects of resveratrol on the growth and polyamine metabolism of CaCo-2 human colon cancer cells. These CaCo-2 human colon cancer cells were treated with 25M resveratrol and were found to cause a 70 growth inhibition. The cell cycle was halted between the synthesis (S) and the gap-2 (G2) phase. Also, resveratrol caused a significant decrease of ornithine decarboxylase (ODC) activity, a key enzyme of polyamine biosynthesis (which is enhanced in cancer growth), indicating that polyamines might represent one of several targets involved in the anti-proliferative effects of resveratrol.

In another study, vaticanol C, a resveratrol tetramer isolated from the stem bark of Vatica rassak, was found to markedly suppress growth of cancer cells by an induction of apoptosis, which was characterized by nuclear changes and DNA ladder formation, in three different human colon cancer cell lines.

Again, resveratrol has been found to increase caspase-3 (apoptotic protein) activities at 24 and 48 hour post-treatments. This study, conducted by Wolter et al (2001), investigated the effect of resveratrol on the human colonic adenocarcinoma CaCo-2 cells and was found to inhibit growth and proliferation of CaCo-2 cells in a dose-dependent manner (12.5-200M) (Wolter et al, 2001). Resveratrol also, during the course of this experiment, disturbed cell cycle progression from the S to G2 phase at 50M, whereas higher concentrations led to reversal of the S phase arrest. Levels of cyclin D1 and cyclin-dependent kinase (cdk) 4 proteins were found to decrease by resveratrol-treatment. The conclusion of this study is that resveratrol exerts its chemopreventive activities by inhibiting the cell cycle.

6. Resveratrol and Other Cancers
Resveratrol exerts chemopreventive effects on almost all cancers. Apart from the effects listed above, resveratrol also inhibits the development of some other cancers.

The role of resveratrol in preventing blood cancers was tested by Surh et al (1999). In this study conducted on cultured human promyelocytic leukemic cells, the growth inhibitory and antiproliferative properties of resveratrol were suggested to be attributable to its induction of apoptotic cell death as determined by morphological and ultrastructural changes, internucleosomal DNA fragmentation, and increased proportion of the sub-diploid cell population coupled with the fact that resveratrol treatment resulted in a gradual decrease in the expression of anti-apoptotic Bcl-2.

Another study has shown that resveratrol also exerts its antiproliferative effects on thyroid cancer cell lines. The experiment studied the effects of resveratrol on two papillary thyroid carcinoma (PTC) and two follicular thyroid carcinoma (FTC) cell lines. The results showed activation and nuclear translocation of mitogen activated protein kinase (MAPK) viz. extracellular signal-regulated kinase (ERK)-1 and -2. Cellular abundance of the oncogene suppressor protein p53, serine phosphorylation of p53, and abundance of c-fos, c-jun, and p21 mRNAs were also increased by resveratrol. It was therefore concluded that resveratrol induces the apoptosis of papillary and follicular cell lines in thyroid carcinomas.

Not much has been done as regards the role of resveratrol in preventing liver cancers. However, Carbo et al (1999) demonstrated that resveratrol administration to rats inoculated with a fast growing tumor (the Yoshida AH-130 ascites hepatoma) caused a very significant decrease (25) in the tumor cell content. This was presumed to be due to the inhibition of the gap-2 (G2)  Mitosis phase of the cell cycle. Also, flow cytometric analysis of the tumor cell population revealed the existence of an aneuploid peak (representing 28 of total), which suggested that resveratrol causes apoptosis in the tumor cell population resulting in a decreased cell number. Sun et al (2002) demonstrated that resveratrol inhibited the growth of hepatoma cells line H22 in a dose- and time-dependent manner via the induction of apoptosis.

Conclusion
Several experiments have confirmed the fact that resveratrol, a phytoalexin (polyphenolic antioxidant), indeed has antiproliferative effects on cancers. They have also shown that apart from its role in preventing cardiovascular diseases, it inhibits all the three stages of malignant transformation initiation, promotion and progression. At the present, epidemiological studies on resveratrol have suggested that it merits human consumption in food sources such as red wine, berries, grapes, etc. The success of resveratrol as a chemopreventive agent depends on vigorous and extensive testing on suitable human populations. Its pharmacodynamics and pharmacokinetics needs to be extensively tested. Resveratrol has shown remarkable potentials in the fight against cancer. However, there is still a lot to be done as regards its use as a potent and efficacious chemopreventive agent against cancer.

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